Ashraf Sadaf, Bouhana Karyn S, Pheneger Jed, Andrews Steven W, Walsh David A
Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, UK.
Array Biopharma, Boulder, CO, USA.
Arthritis Res Ther. 2016 May 4;18(1):97. doi: 10.1186/s13075-016-0996-z.
Inflammation is an essential component of arthritis pain. Nerve growth factor (NGF) plays a key role in acute and chronic pain states especially those associated with inflammation. NGF acts through tropomyosin-receptor-kinase A (TrkA). NGF blockade has reduced arthritis pain in clinical trials. We explored the mechanisms within the joint which may contribute to the analgesic effects of NGF by selectively inhibiting TrkA in carrageenan-induced or collagen-induced joint pain behaviour. The goal of the current study was to elucidate whether inflammation is central to the efficacy for NGF blockade.
Rats were injected in their left knees with 2 % carrageenan or saline. Collagen-induced arthritis (CIA) was induced by intradermal injections of a mixture of bovine type II collagen (0.2 mg) and incomplete Freund's adjuvant (0.2 mg). Oral doses (30 mg/kg) of AR786 or vehicle control were given twice daily after arthritis induction. Ibuprofen-treated (35 mg/kg, orally, once daily) rats with CIA were used as positive analgesic controls. Pain behaviour was measured as hind-limb weight-bearing asymmetry and hind-paw withdrawal thresholds to von Frey hair stimulation (carrageenan synovitis), or withdrawal to joint compression using a Randall Selitto device (CIA). Inflammation was measured as increased knee joint diameter and by histopathological analysis.
Intra-articular injections of carrageenan or induction of CIA was each associated with pain behaviour and synovial inflammation. Systemic administration of the TrkA inhibitor AR786 reduced carrageenan-induced or CIA-induced pain behaviour to control values, and inhibited joint swelling and histological evidence of synovial inflammation and joint damage.
By using two models of varying inflammation we demonstrate for the first time that selective inhibition of TrkA may reduce carrageenan-induced or CIA-induced pain behaviour in rats, in part through potentially inhibiting synovial inflammation, although direct effects on sensory nerves are also likely. Our observations suggest that inflammatory arthritis causes pain and the presence of inflammation is fundamental to the beneficial effects (reduction in pain and pathology) of NGF blockade. Further research should determine whether TrkA inhibition may ameliorate human inflammatory arthritis.
炎症是关节炎疼痛的一个重要组成部分。神经生长因子（NGF）在急性和慢性疼痛状态中起关键作用，尤其是那些与炎症相关的疼痛状态。NGF通过原肌球蛋白受体激酶A（TrkA）发挥作用。在临床试验中，NGF阻断已减轻了关节炎疼痛。我们通过在角叉菜胶诱导或胶原诱导的关节疼痛行为中选择性抑制TrkA，探索了关节内可能有助于NGF镇痛作用的机制。本研究的目的是阐明炎症对于NGF阻断疗效是否至关重要。
给大鼠左膝注射2%角叉菜胶或生理盐水。通过皮内注射牛II型胶原（0.2mg）和不完全弗氏佐剂（0.2mg）的混合物诱导胶原诱导性关节炎（CIA）。关节炎诱导后，每天两次给予AR786口服剂量（30mg/kg）或载体对照。用布洛芬治疗（35mg/kg，口服，每日一次）的CIA大鼠作为阳性镇痛对照。疼痛行为通过后肢负重不对称以及对von Frey毛发刺激的后爪撤阈值（角叉菜胶性滑膜炎）来测量，或者使用Randall Selitto装置通过对关节压迫的撤回来测量（CIA）。炎症通过膝关节直径增加和组织病理学分析来测量。
关节内注射角叉菜胶或诱导CIA均与疼痛行为和滑膜炎症相关。全身给予TrkA抑制剂AR786可将角叉菜胶诱导或CIA诱导的疼痛行为降低至对照值，并抑制关节肿胀以及滑膜炎症和关节损伤的组织学证据。
通过使用两种炎症程度不同的模型，我们首次证明选择性抑制TrkA可能会降低大鼠角叉菜胶诱导或CIA诱导的疼痛行为，部分原因可能是通过抑制滑膜炎症，尽管对感觉神经的直接作用也很可能存在。我们的观察结果表明，炎性关节炎会引起疼痛，并且炎症的存在对于NGF阻断的有益效果（减轻疼痛和病理改变）至关重要。进一步的研究应确定抑制TrkA是否可改善人类炎性关节炎。
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